Gilbert was born in Zanesville, Ohio, the middle of three sons, and was named after the statesman Lewis Cass, to whom he was distantly related. Gilbert’s father General Samuel A. Gilbert was a Union veteran of the American Civil War and a surveyor for the United States Coast Survey. His uncle was Union Gen. Charles Champion Gilbert. When he was nine, Gilbert’s family moved to St. Paul, Minnesota, where he was raised by his mother after his father died. He attended preparatory school but dropped out of Macalester College. He began his architectural career at age 17 by joining the Abraham M. Radcliffe office in St. Paul. In 1878, Gilbert enrolled in the architecture program at MIT.

The completion of the Minnesota capitol gave Gilbert his national reputation and in 1898 he permanently moved his base to New York. His breakthrough commission was the design of the Alexander Hamilton U.S. Custom House in New York City, which now houses the George Gustav Heye Center. Gilbert served on the U.S. Commission of Fine Arts from 1910 to 1916. In 1906 he was elected into the National Academy of Design as an Associate member, and became a full Academician in 1908. Gilbert served as President of the Academy from 1926 to 1933.